An efficient synthesis of polysubstituted tetrahydropyrimidines using acidic Al2O3 as solid media

doi:10.5246/jcps.2016.06.047

Abstract

Abstract:

A series of polysubstituted tetrahydropyrimidines were synthesized in moderate to good yields via a one-pot, four-componentreaction of an alkyne, formaldehyde, and amines in solid media acidic Al₂O₃. The advantages of this protocol include mild reaction conditions, broad substrate scope, and environmentally friendly reaction media.

Key words: Tetrahydropyrimidine, Solid media, Acidic Al2O3, Multi-component reaction, Green chemistry

CLC Number:

R916.42

Supporting:

An efficient synthesis of polysubstituted tetrahydropyrimidines using acidic Al₂O₃ as solid media

Tian Gao, Ling Ji, Xin Wang^*, Runtao Li^*

State Key Laboratory of Nature and Biomimtic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

General information

¹H NMR spectra were recorded on a Bruker AVANCE III-400 spectrometer. Chemical shifts (in ppm) were referenced to the solvent residual signal (δ = 7.26 ppm) of CDCl_3. ¹³C NMR spectra were obtained by using the same NMR spectrometer and were calibrated to CDCl₃(δ = 77.00 ppm). High Resolution Mass spectra were recorded using a Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (APEX IV, Bruker). Unless otherwise noted, materials obtained from commercial suppliers were used without further purification. Column chromatography was carried out on silica gel (particle size 200–300 mesh ASTM).

A. Experiment procedure and characterization data for products

a. General procedure for the synthesis of tetrahydropyrimidines

Amine 2 (1 mmol) was added to a uniform mixture of compound 1 (1 mmol) and 0.75 g of acidic Al₂O₃. The mixture was stirred at room temperature for 5 min (ground if necessary). The mixture of formaldehyde (4 mmol), amine 3 (1 mmol), and 0.75 g of acidic Al₂O₃ was ground at room temperature until full conversion of 3. Then the two mixtures were transferred into a round-bottom flask and stirred at 60 ^oC for 2–5 h using a magnetic stirrer. After completion, 3 mL of CH₂Cl₂ was added to the reaction mixture, which was then stirred and filtered. The solvent was evaporated in vacuo to afford the crude product. Chromatography on silica gel (ethyl acetate–petroleum ether) gave corresponding product 4 as a yellow crystal or liquid.

b. Characterization data

Diethyl 1,3-diphenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4a)

Yellow crystal, mp: 85–86 ^oC. ¹H NMR (400 MHz, CDCl₃) δ: 7.31–7.17 (m, 5H), 7.06–7.02 (m, 2H), 6.96–6.88 (m, 3H), 4.93 (s, 2H), 4.29 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.6, 163.9, 148.3, 146.5, 143.7, 129.3, 129.2, 126.4, 125.3, 121.0, 117.7, 100.9, 68.7, 61.6, 60.2, 47.6, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₂H₂₅N₂O₄ [M+H]⁺: 381.1809; Found: 381.1805.

Diethyl 1,3-di-p-tolyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4b) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.08 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.86 (s, 2H), 4.24 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 163.9, 146.5, 146.0, 143.7, 130.6, 129.8, 129.1, 126.4, 125.3, 118.0, 100.5, 69.1, 61.6, 60.2, 47.8, 20.5, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M+H]⁺: 409.2122; Found: 409.2121.

Diethyl 1,3-bis(4-methoxyphenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4c)

Yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 6.96 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 4.78 (s, 2H), 4.20 (s, 2H), 4.20 (q, J = 7.3 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.8, 164.0, 158.3, 154.7, 147.4, 142.4, 136.3, 127.7, 120.3, 114.5, 114.2, 97.8, 70.6, 61.5, 60.0, 55.6, 55.4, 47.9, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₆ [M+H]⁺: 441.2020; Found: 441.2027.

Diethyl 1,3-dibenzyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4d)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.38–7.17 (m, 10H), 4.39 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 3.64 (s, 2H), 3.60 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 165.2, 148.1, 138.1, 136.4, 128.8, 128.7, 128.3, 128.0, 127.9, 127.2, 92.6, 66.1, 62.1, 59.6, 57.1, 54.1, 48.6, 14.4, 13.9. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M+H]⁺: 409.2122; Found: 409.2127.

Diethyl 1,3-dibutyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4e)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 4.36 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.96 (s, 2H), 3.50 (s, 2H), 3.03 (t, J = 7.7 Hz, 2H), 2.53 (t, J = 7.4 Hz, 2H), 1.53 (dq, J = 14.9, 7.7 Hz, 4H), 1.43 – 1.34 (m, 5H), 1.29 (dd, J = 14.9, 7.4 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.93 (dt, J = 10.5, 7.4 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 165.0, 148.1, 91.4, 67.7, 61.8, 59.4, 52.5, 50.8, 48.4, 31.3, 30.1, 20.5, 19.9, 14.4, 14.0, 14.0, 13.7. HRMS (ESI): m/z calcd for C₁₈H₃₃N₂O₂ [M + H]⁺: 341.2435; Found: 341.2438.

Diethyl 1,3-diallyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4f)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 5.94–5.73 (m, 2H), 5.28–5.15 (m, 4H), 4.36 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.53 (s, 2H), 3.19 (d, J = 6.4 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.2, 164.9, 147.8, 135.0, 133.3, 118.4, 118.2, 92.4, 66.2, 61.9, 59.5, 55.9, 53.1, 48.3, 14.4, 13.9. HRMS (ESI): m/z calcd for C₁₆H₂₅N₂O₄ [M + H]⁺: 309.1809; Found: 309.1811.

Diethyl 1-(4-chlorophenyl)-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4g) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.17 (m, 5H), 7.03 (d, J = 7.4 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.91 (s, 2H), 4.26 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.6, 163.9, 148.3, 146.5, 143.7, 129.2, 129.2, 126.4, 125.3, 121.0, 117.7, 100.9, 77.3, 77.0, 76.7, 68.7, 61.6, 60.2, 47.6, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₂H₂₄ClN₂O₄ [M+H]⁺: 415.1419; Found: 415.1426.

Diethyl 1-(4-methoxyphenyl)-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4h). Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.26 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 4.85 (s, 2H), 4.21(s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.8, 163.9, 154.7, 146.6, 143.7, 142.3, 129.1, 126.4, 125.4, 120.2, 114.5, 100.1, 70.2, 61.5, 60.1, 55.6, 48.2, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₃H₂₇N₂O₅ [M + H]⁺: 411.1915; Found: 411.1915.

Diethyl 3-phenyl-1-(o-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4i). Yellow crystal, mp: 91–92 ºC. ¹H NMR (400 MHz, CDCl₃) δ: 7.30–7.11 (m, 6H), 7.02 (t, J = 6.6 Hz, 3H), 4.65 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.10（s, 2H）, 4.08 (q, J = 13.8, 7.1 Hz, 2H), 2.24 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.8, 164.2, 148.2, 146.5, 143.7, 132.7, 131.2, 129.0, 126.7, 126.2, 125.4, 124.2, 121.1, 101.2, 69.9, 61.6, 60.1, 49.2, 18.1, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₃H₂₇N₂O₄ [M+H]⁺: 395.1965; Found: 395.1968.

Diethyl 3-phenyl-1-(m-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4j). Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.31 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 8.3 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 6.73 (d, J = 6.3 Hz, 3H), 4.92 (s, 2H), 4.28 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 164.0, 148.2, 146.4, 143.8, 139.0, 129.2, 129.1, 126.4, 125.2, 121.8, 118.3, 114.6, 101.2, 68.3, 61.6, 60.2, 47.8, 21.7, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₃H₂₇N₂O₄ [M+H]⁺: 395.1965; Found: 395.1975.

Diethyl 3-phenyl-1-(p-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4k) Yellow crystal, mp: 83–84 ^oC. ¹H NMR (400 MHz, CDCl3) δ: 7.28 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 5.8 Hz, 4H), 6.85 (d, J = 8.4 Hz, 2H), 4.89 (s, 2H), 4.25 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 163.9, 146.5, 146.0, 143.7, 130.6, 129.8, 129.1, 126.4, 125.3, 118.0, 100.5, 69.1, 61.6, 60.2, 47.8, 20.5, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₃H₂₇N₂O₄ [M+H]⁺: 395.1965; Found: 395.1974.

Diethyl 1-(3,5-dimethylphenyl)-3-phenyl-1,2,3,6-tetrahydropyrimidine -4,5-dicarboxylate (4l) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.32 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 6.55 (s, 1H), 6.52 (s, 2H), 4.89 (s, 2H), 4.26 (s, 2H), 4.22(q, J = 7.1 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.22 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 164.0, 148.2, 146.2, 143.8, 138.8, 129.2, 126.3, 125.2, 122.7, 115.9, 115.2, 101.6, 68.1, 61.5, 60.2, 48.0, 21.5, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M+H]⁺: 409.2122; Found:409.2118.

Diethyl 1-butyl-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4m) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.32 (t, J = 7.7 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H), 4.39 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 2.77 – 2.59 (m, 2H), 1.45 (dt, J = 14.7, 7.2 Hz, 2H), 1.34 (dt, J = 14.8, 7.3 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.1, 145.7, 144.0, 129.2, 126.2, 125.2, 98.0, 70.6, 61.5, 59.9, 52.2, 48.9, 30.0, 20.4, 14.3, 13.9, 13.6. HRMS (ESI): m/z calcd for C₂₀H₂₉N₂O₄ [M+H]⁺: 361.2122; Found: 361.2128.

Diethyl 1-isobutyl-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4n) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.30 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 4.35 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 2.41 (d, J = 7.3 Hz, 2H), 1.68 (dp, J = 13.5, 6.7 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.89 (s, 3H), 0.87 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.1, 145.8, 144.1, 129.1, 126.2, 125.2, 98.1, 71.3, 61.5, 60.6, 59.9, 49.3, 26.5, 20.6, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₀H₂₉N₂O₄ [M + H]⁺: 361.2122; Found: 361.2111.

Diethyl 1-(tert-butyl)-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4o) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.30 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 4.33 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.66 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.12 (s, 9H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.0, 164.5, 145.9, 143.9, 129.1, 125.7, 124.5, 103.7, 66.5, 61.4, 60.0, 53.6, 44.1, 27.1, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₀H₂₉N₂O₄ [M + H]⁺: 361.2122; Found: 361.2128.

Diethyl 1-allyl-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4p) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.29 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.4 Hz, 2H), 5.81 (ddt, J = 16.8, 10.3, 6.4 Hz, 1H), 5.13–5.00 (m, 2H), 4.37 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 3.28 (d, J = 6.4 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.2, 164.1, 145.7, 143.8, 134.6, 129.1, 126.2, 125.2, 118.6, 98.0, 69.5, 61.5, 60.0, 55.6, 48.9, 14.3, 13.6. HRMS (ESI): m/z calcd for C₁₉H₂₅N₂O₄ [M + H]⁺: 345.1809; Found: 345.1812.

Diethyl 1-benzyl-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4q) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.52–7.08 (m, 9H), 4.37 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 3.75 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.1, 145.7, 143.8, 137.9, 129.1, 128.9, 128.3, 127.3, 126.2, 125.2, 98.1, 69.7, 61.6, 60.0, 56.8, 49.1, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₃H₂₇N₂O₄ [M+H]⁺: 395.1965; Found: 395.1972.

Diethyl 1-benzyl-3-(o-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4r). Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.40–7.27 (m, 5H), 7.26–7.15 (m, 4H), 4.37 (d, J = 11.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 11.6 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.91 (d, J = 13.4 Hz, 2H), 3.72 (s, 2H), 2.34 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 164.0, 147.2, 141.2, 138.1, 137.1, 131.0, 129.1, 128.8, 128.4, 128.1, 127.3, 126.4, 94.1, 69.7, 61.3, 59.8, 57.2, 48.3, 18.2, 14.3, 13.5. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M+H]⁺: 409.2122; Found: 409.2134.

Diethyl 1-benzyl-3-(m-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4s)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.28–7.14 (m, 5H), 6.97 (dd, J = 15.9, 6.7 Hz, 3H), 4.34 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 3.71 (s, 2H), 2.31 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.2, 145.8, 143.8, 139.1, 138.0, 128.9, 128.9, 128.3, 127.3, 127.0, 125.8, 122.2, 97.7, 69.8, 61.5, 59.9, 56.8, 49.0, 21.3, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M + H]⁺: 409.2122; Found: 409.2131.

Diethyl 1-benzyl-3-(p-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4t) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.31–7.23 (m, 5H), 7.11 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.34 (s, 2H), 4.16 (d, J = 7.1 Hz, 2H), 4.09 (d, J = 7.2 Hz, 2H), 3.85 (s, 2H), 3.73 (s, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.2, 146.2, 141.1, 138.0, 136.3, 129.7, 128.9, 128.3, 127.3, 125.4, 96.7, 69.9, 61.5, 59.9, 56.8, 48.8, 21.0, 14.3, 13.6. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₄ [M+H]⁺: 409.2122; Found: 409.2132.

Diethyl 1-benzyl-3-(4-chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4u) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.29–7.23 (m, 7H), 7.09 (d, J = 8.6 Hz, 2H), 4.31 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 3.73 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.1, 164.0, 145.1, 142.6, 137.7, 131.6, 129.3, 128.8, 128.4, 127.4, 126.2, 99.6, 69.6, 61.8, 60.1, 56.8, 49.1, 14.3, 13.7. HRMS (ESI): m/z calcd for C₂₃H₂₆ClN₂O₄ [M + H]⁺: 429.1576; Found: 429.1587.

Diethyl 1-benzyl-3-(4-nitrophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4v)

Orange oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.18 (d, J = 9.1 Hz, 2H), 7.25–7.19 (m, 3H), 7.14 (d, J = 9.1 Hz, 2H), 7.10 (dd, J = 6.5, 2.9 Hz, 2H), 4.41 (s, 2H), 4.20 (dq, J = 14.5, 7.2 Hz, 4H), 3.77 (s, 2H), 3.73 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 165.7, 150.6, 143.7, 142.1, 140.1, 137.0, 128.7, 128.5, 127.6, 125.1, 121.9, 107.7, 69.0, 62.2, 60.7, 56.8, 49.9, 14.2, 13.7. HRMS (ESI): m/z calcd for C₂₃H₂₆N₃O₆ [M+H]⁺: 440.1816; Found: 440.1824.

Diethyl 1-benzyl-3-(4-methoxyphenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4w) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.38–7.20 (m, 7H), 6.93–6.87 (m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.02 (d, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.83 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 163.9, 155.9, 147.1, 138.5, 131.4, 129.0, 128.9, 128.7, 128.3, 127.2, 120.4, 111.8, 94.5, 69.2, 61.3, 59.7, 56.7, 55.7, 48.4, 14.4, 13.6. HRMS (ESI): m/z calcd for C₂₄H₂₉N₂O₅ [M+H]⁺: 425.2071; Found: 425.2079.

Diethyl 1-benzyl-3-(naphthalen-1-yl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4x) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.11 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.60–7.41 (m, 4H), 7.39 (d, J = 7.4 Hz, 2H), 7.33 – 7.27 (m, 2H), 7.26–7.20 (m, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.25 (d, J = 11.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.00 (q, J = 13.4 Hz, 2H), 3.84 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.63 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.0, 147.4, 139.4, 138.0, 134.5, 131.2, 128.8, 128.4, 128.3, 128.2, 127.3, 126.8, 126.6, 126.3, 125.2, 123.7, 96.2, 70.8, 61.2, 59.9, 57.3, 48.7, 14.3, 13.2. HRMS (ESI): m/z calcd for C₂₇H₂₉N₂O₄ [M+H]⁺: 445.2122; Found: 445.2132.

Diethyl 3-allyl-1-benzyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4y). Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.40–7.29 (m, 5H), 5.77 (ddt, J = 15.9, 9.8, 6.1 Hz, 1H), 5.18–5.12 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.73 (s, 2H), 3.62 (d, J = 6.1 Hz, 2H), 3.58 (s, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 166.3, 164.9, 147.9, 138.1, 133.1, 129.0, 128.4, 127.3, 118.5, 92.5, 66.3, 61.9, 59.6, 57.1, 53.2, 48.4, 14.4, 14.0. HRMS (ESI): m/z calcd for C₂₀H₂₇N₂O₄ [M+H]⁺: 359.1965; Found:359.1959.

Methyl 1,3-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4z)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (s, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.24 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 5.07 (s, 2H), 4.29 (s, 2H), 3.75 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 167.2, 148.8, 144.2, 140.5, 129.7, 129.3, 123.7, 121.1, 117.9, 117.8, 99.7, 64.6, 51.0, 47.5. HRMS (ESI): m/z calcd for C₁₈H₁₉N₂O₂ [M+H]⁺: 295.1441; Found: 295.1440.

1-(1,3-diphenyl-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (4aa) Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (s, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.24 – 7.15 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.89 (t, J = 7.3 Hz, 1H) 5.08 (s, 2H), 4.32 (s, 2H), 2.23 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 194.0, 148.5, 144.2, 142.3, 129.9, 129.3, 124.4, 121.1, 118.5, 117.7, 112.0, 65.0, 46.9, 23.9. HRMS (ESI): m/z calcd for C₁₈H₁₉N₂O [M+H]⁺: 279.1492; Found: 279.1498.

c. NMR Spectra:

4aa

Tian Gao, Ling Ji, Xin Wang, Runtao Li. An efficient synthesis of polysubstituted tetrahydropyrimidines using acidic Al2O3 as solid media[J]. Journal of Chinese Pharmaceutical Sciences, DOI: 10.5246/jcps.2016.06.047.

References

[1] (a) Dunbar, P.G.; Durant, G.J.; Fang, Z.; Abuh, Y.F.; El-Assadi, A.A.; Ngur, D.O.; Periyasamy, S.; Hoss, W.P.; Messer, W.S.Jr. J. Med. Chem. 1993, 36, 842-847; (b) Dunbar, P.G.; Durant, G.J.; Rho, T.; Ojo, B.; Huzl, J.J. III.; Smith, D.A.; El-Assadi, A.A.; Sbeih, S.; Ngur, D.O. J. Med. Chem. 1994, 37, 2774-2782; (c) Messer, W.S.Jr.; Abuh, Y.F.; Liu, Y.; Periyasamy, S.; Ngur, D.O.; Edgar, M.A.N.; El-Assadi, A.A.; Sbeih, S.; Dunbar, P.G.; Roknich, S. J. Med. Chem. 1997, 40, 1230-1246.
[2] (a) Lun, Y.N.; Xia, H.; Zhang, Q.; Yu, C.L.; Chen, N.N.; Li, X.J.; Liu, S.W.; Lei, L.S. Int. Immunopharmacol. 2013, 17, 168-177; (b) Lokwani, D.K.; Mokale, S.N.; Shinde, D.B. Eur. J. Med. Chem. 2014, 73, 233-242; (c) Pattarini, R.; Smeyne, R.J.; Morgan, J.I. Neuroscience. 2007, 145 , 654-668.
[3] (a) Abdel-Aziz, H.; Wadie, W.; Abdallah, D.M.; Lentzen, G.; Khayyal, M.T. Phytomedicine. 2013, 20, 585-591; (b) Gein, V.L.; Fedotov, A.Y.; Zamaraeva, T.M.; Bobyleva, A.A.; Kasimova, N.N.; Odegova, T.F. Pharm. Chem. J. 2013, 46, 720-722; (c) Gein, V.L.; Kholkin, I.V.; Zamaraeva, T.M.; Voronina, E.V.; Vakhrin, M.I. Pharm. Chem. J. 2012, 46, 114-116; (d) Patel, P.; Chintha, C.; Ghate, M.; Bhatt, H.; Vyas, V. Med. Chem. Res. 2014, 23, 2955-2963.
[4] (a) Nair, A.C.; Jayatilleke, P.; Wang, X.; Miertus, S.; Welsh, W.J. J. Med. Chem. 2002, 45, 973-983; (b) Rodina, A.; Vilenchik, M.; Moulick, K.; Aguirre, J.; Kim, J.; Chiang, A.; Litz, J.; Clement, C.C.; Kang, Y.L.; She, Y.H. Nat. Chem. Biol. 2007, 3, 498-507.
[5] (a) Zhu, Q.H.; Huang, L.; Su, J.; Liu, S.W. Chem. Commun. 2014, 50, 1107; (b) Zhu, Q.H.; Huang, L.; Chen, Z.P.; Zheng, S.C.; Lv, L.Y.; Zhu, Z.B.; Cao, D.R.; Jiang, H.F.; Liu, S.W. Chem. Eur. J. 2013, 19, 1268-1280.
[6] (a) Martens, T.; Souquet, F. J. Chem. Res. Synop. 1993, 7, 264-265; (b) Moehrle, H.; Reinhardt, H.W. Arch. Pharm. 1982, 315, 716-723.
[7] Lamazouere, A.M.; Sotiropoulos, J. Tetrahedron. 1981, 37, 2451-2457.
[8] Fry, J.L.; Rahaim, R.J.Jr.; Maleczka, R.E.Jr. e-EROS Encyclopedia of Reagents for Organic Synthesis, John Wiley& Sons: New York, 2001.
[9] Zhang, M.; Jiang, H. F.; Liu, H. L.; Zhu, Q.H. Org. Lett. 2007, 9, 4111-4113.
[10] Kidwai, M.; Mishra, N.K.; Bhatnagar, D.; Jahan, A. Green Chem. Lett. Rev. 2011, 4, 109-115.
[11] Zhu, Q.H.; Jiang, H.F.; Li, J.H.; Zhang, M.; Wang, X.J.; Qi, C.R. Tetrahedron. 2009, 65, 4604-4613.
[12] Das, B.; Kanth, B.S.; Shinde, D.B.; Kamble, V.T. Helv. Chim. Acta. 2011, 94, 2087-2091.
[13] Das, B.; Shinde, D.; Kanth, B.; Satyalakshmi, G. Synthesis. 2010, 2010, 2823-2827.
[14] Darandale, S.N.; Pansare, D.N.; Mulla, N.A.; Shinde, D.B. Bioorg. Med. Chem. Lett. 2013, 23, 2632-2635.
[15] Zhu, Q.H.; Huang, L.; Chen, Z.P.; Zheng, S.C.; Lv, L.Y.; Zhu, Z.B.; Cao, D.R.; Jiang, H.F.; Liu, S.W. Chem. Eur. J. 2013, 19, 1268-1280.
[16] Kidwai, M.; Mishra, N.K.; Bhardwaj, S. J. Iranian. Chem. Soc. 2013, 10, 695-699.
[17] (a) Liu, Y.P.; Li, J.M.; Wang, X.; Cheng, T.M.; Li, R.T. Tetrahedron. 2013, 69, 5242-5247; (b) Ai, X.; Wang, X.; Liu, J.M.; Ge, Z.M.; Cheng, T.M.; Li, R.T. Tetrahedron. 2010, 66, 5373-5377; (c) Xia, S.; Wang, X.; Ge, Z.M.; Cheng, T.M.; Li, R.T. Tetrahedron. 2009, 65, 1005-1009.